Inhaled steroids reduce ACE2 expression in COPD lungs

As the COVID-19 pandemic spreads across the world, its primary manifestation in severe or critical disease remains respiratory, beginning with pneumonitis, progressing through acute respiratory distress syndrome to terminal respiratory failure. At present, therefore, people who already have chronic lung disease, including asthma and chronic obstructive pulmonary disease (COPD), are at very high risk for mortality due to COVID-19 and must be kept safe from acquiring the infection.

This guideline is based on the vast breadth of clinical experience, which shows that such patients are easily infected by respiratory viruses and rapidly deteriorate as a result. On the other hand, the prevalence of COPD and asthma are lower among COVID-19 patients than in the general population, though COPD is linked to a higher risk of complicated disease and death.

The Effects of ICS

A new study by scientists at Imperial College London, University of Newcastle and Prokarium, and published on the preprint server bioRxiv* in June 2020 examines the role played by inhaled corticosteroids (ICS) in the risk of acquisition of COVID-19 infection by COPD patients. ICS have long been the linchpin of therapy for disease of the airways, primarily due to their striking anti-inflammatory effects and protective effects against exacerbations of these chronic conditions. This could mean that they prevent infection or modulate virus-induced inflammation, thus preventing the emergence of symptoms.

On the other hand, ICS also reduce innate immunity to respiratory viruses, as has been shown in the case of influenza and rhinovirus infections, which could allow the virus to replicate more. It is worth noting that ICS had a protective effect against seasonal coronavirus and SARS-CoV-2. The current study aimed to uncover the real effect of ICS on the immune response to SARS-CoV-2 and how their use affects the risk of COVID-19 in patients with COPD or asthma.

Variation in ACE2 Expression in Lung Disease

SARS-CoV-2 enters the host cell via the ACE2 receptor (angiotensin-converting enzyme 2), while the serine protease TMPRSS2 cleaves the spike (S) protein to enable host cell -viral membrane fusion, to cause active infection. Recent research shows that the expression of ACE2 is higher in the respiratory epithelium of smokers as well as COPD patients. This could potentially account for the worse outcomes in these individuals compared to the general population.

However, asthmatic patients have a lower expression of ACE2, perhaps because of type 2 cytokine release or ICS use, or even because it is co-expressed with interferon stimulating genes (ISG). Recent research shows that ACE2 is one of the ISGs in the respiratory epithelium in humans, which shows the potential importance of antiviral immune responses in the expression of ACE2 in the lungs.

The researchers have earlier discovered the powerful inhibitory effect of ICS on the expression of type I interferons (IFN) and ISGs in COPD, both in vivo and in vitro. Hence, it is possible that ICS could lead to the suppression of IFN, which in turn results in the reduction of ACE2 expression in the lungs. This could thus affect the susceptibility of COPD patients to the virus.

ACE2 in COPD: The Effects of ICS

The current study included 36 COPD subjects, examining the ACE2 mRNA in their sputum, with 18 each being currently on or not on ICS. Sputum ACE2 mRNA was found in 22 patients, showing a significant reduction in patients on ICS compared to the others. The serine protease TMPRSS2 was also expressed in all the sputum cells, from those on ICS and those without. This protein is required for viral entry. The alternative receptor for SARS-CoV, namely, CD147, was also uniformly detectable in all subjects.

A mouse model was used where the ICS fluticasone propionate was given to the animals at a dosage, which would activate lung glucocorticoid receptors. The aim was to see if it would also stimulate ACE2 expression. The researchers found that it reduced ACE2 expression at 8 hours, lasting for 24 hours, but not observable after 48 hours.

However, the ICS did not affect either TMPRSS2 or CD147. When the fluticasone was reduced by 10-fold, it no longer affected either glucocorticoid receptors or ACE2 expression. Repeating the experiment with other conventional ICS like beclomethasone or budesonide showed the same effect with all of them. When the lung was homogenized and analyzed for ACE2 protein content, the same pattern of suppression of total ACE2 was observed.

IFN and ACE2

The next step was to measure the mRNA of ISG and the IFN concentrations in bronchoalveolar lavage (BAL). The researchers found that the expression of ACE2 in the lung corresponded to these parameters. Based on earlier data, they theorized that the reduced expression of ACE2 in response to ICS is because the latter suppresses cell signaling via IFN-mediated pathways. If so, it should be possible to reverse it by IFN-β administration – which was in fact the case.

Moreover, mice that lacked IFN signaling had a significant, though a small decline in lung ACE2 expression, supporting the earlier findings. Since it is already known that ACE2 is expressed in the epithelium of the nose and airways and that ICS also suppresses primarily lung epithelial immunity, they looked for suppression of ACE2 when bronchial epithelial cells in culture were exposed to ICS. They found that while COPD-derived cells had a threefold increase in ACE2 expression, as compared to healthy non-smoking subjects, the administration of ICS reduced it by 75%.

Again, a mouse model showed that lung ACE2 increased 15-fold in elastase-treated mice (which are similar to human COPD subjects), but reduced after a single dose of ICS.

The Implications

The current study shows that ICS reduces ACE2 levels in human and animal lung tissue, in response to the suppression of type I IFNs, indicating a possible protective effect of ICS against COVID-19 in COPD patients. However, in view of the potentially harmful decline in protective innate immunity with ICS, more research is called for to clarify the exact nature of ICS effects on COVID-19 susceptibility in this group of patients, and to, indeed, define the outcome of increased or decreased ACE2 levels on the infection.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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